Crystalline duloxetine hydrochloride

ABSTRACT

Crystalline duloxetine hydrochloride, compositions containing the same and methods for the production thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from Great Britain Application NumberGB 0612506.6, filed 23 Jun. 2006.

FIELD OF THE INVENTION

The present invention relates to crystalline duloxetine hydrochloride,to compositions containing the same and to methods for the formationthereof.

BACKGROUND OF THE INVENTION

Duloxetine hydrochloride is a potent dual reuptake inhibitor ofserotonin and norepinephrine possessing comparable affinities in bindingto serotonin and norepinephrine transport sites. Duloxetinehydrochloride has, therefore, been implicated in the treatment ofvarious diseases related to these effects. For example, duloxetinehydrochloride is the active ingredient of the antidepressant drugCymbalta® It is also used to target pain related to diabetic neuropathyand stress urinary incontinence.

Preparation of duloxetine hydrochloride has been disclosed elsewhere,for example in U.S. Pat. No. 5,023,269. Crystalline forms of the freebase of duloxetine and their preparation have been reported inWO2005/108386. The amorphous form of duloxetine hydrochloride salttogether with its preparation has been reported in WO2005/019199.

There is no generally applicable method for preparing a crystalline formof an amorphous drug. For example, it is impossible to know withoutexperimentation whether any crystalline form of a given compound exists.Even once it has been found that a drug can be crystallised, extensiveexperimentation is usually required before a repeatable and quantifiableprocess is identified from which the crystalline form can be isolated.In this respect, several independently variable conditions, such as thenature of solvent, concentration of solvent and temperature, must becorrectly identified in order to elucidate a suitable process. Indeed,to date, there have been no reports describing isolation or productionof crystalline duloxetine hydrochloride.

It is, therefore, an object of the present invention to providecrystalline forms of duloxetine hydrochloride together with methods forthe production thereof.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention, there is providedcrystalline duloxetine hydrochloride.

According to another aspect of the present invention, there is providedcrystalline duloxetine hydrochloride which exhibits an X-ray diffractionpattern comprising peaks expressed in degrees two-theta at approximately11.95±0.2, 21.44±0.2, 22.12±0.2, 23.08±0.2 and 24.06±0.2. The degree oferror is preferably ±0.1.

According to a further aspect of the present invention, there isprovided crystalline duloxetine hydrochloride which exhibits an X-raydiffraction pattern comprising peaks expressed in degrees two-theta atapproximately 11.95±0.2, 13.93±0.2, 14.5±0.2, 14.76±0.2, 16.19±0.2,17.97±0.2, 18.62±0.2, 18.82±0.2, 20.79±0.2, 21.26±0.2, 21.44±0.2,21.76±0.2, 22.12±0.2, 22.28±0.2, 23.08±0.2, 23.28±0.2, 24.06±0.2,26.31±0.2, 26.94±0.2 and 29.86±0.2. The degree of error is preferably±0.1.

There is also provided by the present invention, crystalline duloxetinehydrochloride which exhibits an X-ray diffraction pattern substantiallythe same as shown in FIG. 1.

Preferably, the crystalline duloxetine hydrochloride has a purity of atleast 95%, more preferably at least 98%.

According to a further aspect of the present invention, there isprovided a method for the preparation of crystalline duloxetinehydrochloride, the method comprising:

-   -   (a) dissolving duloxetine in a first organic solvent to form a        first solution;    -   (b) adding the first solution to a second organic solvent        solution comprising HCl to form a second solution;    -   (c) adding the second solution to a third organic solvent to        form a third solution;    -   (d) allowing duloxetine hydrochloride to crystallize out from        the solution; and    -   (e) collecting the crystallized duloxetine hydrochloride.

Preferably, the first organic solvent is a halogen substituted C₁ to C₆hydrocarbon, more preferably dichloromethane.

In preferred embodiments, the second organic solvent is an alcohol, morepreferably a straight or branched C₁ to C₆ alcohol, further preferablyethanol.

Preferably, the third organic solvent is a C₁ to C₈ hydrocarbon, morepreferably hexane.

Preferably, the duloxetine is dissolved in the first organic solvent ina ratio of about 5 ml first organic solvent for about every 3 g ofduloxetine.

In preferred aspects, the second organic solvent comprises about 20%HCl.

It is also preferred that the first solution is added to the secondorganic solvent at around 0° C. The first solution is preferably addedto the second organic solvent with stirring.

Preferably, the second solution is added to a volume of the thirdorganic solvent in a ratio of about 40 ml third organic solvent forabout every 3 g duloxetine used in step (a).

In order to maximize crystallization, the duloxetine hydrochloride maybe allowed to crystallize out from the solution during a period ofcooling at around 0° C. to around 10° C. Preferably, the duloxetinehydrochloride is allowed to crystallize out from the solution during aperiod of about 10 hours.

Preferably, the crystallized duloxetine hydrochloride is collected byfiltration. The collected crystallized duloxetine hydrochloride ispreferably washed and then dried.

In preferred embodiments, the collected crystallized duloxetinehydrochloride is washed with a C₁ to C₈ hydrocarbon, more preferablyhexane.

Preferably, the collected crystalline duloxetine hydrochloride is driedunder vacuum.

Preferably, the method comprising the following additional steps for thepreparation of duloxetine for use in step (a):

(i) placing duloxetine oxalate into a solution of a fourth organicsolvent and water;

(ii) adding aqueous ammonia solution for dissolving the duloxetineoxalate;

(iii) isolating a separated organic layer;

(iv) washing the organic layer with saturated brine;

(v) drying the organic layer; and

(vi) removing the solvents from the organic layer.

Preferably, the fourth organic solvent is a C₁ to C₆ ester, morepreferably ethyl acetate.

The duloxetine oxalate is preferably placed into a solution of thefourth organic solvent and water at a ratio of about 300 ml fourthorganic solvent and water solution for about every 39 g of duloxetineoxalate.

Preferably, the solution of a fourth organic solvent and water containsabout 1 ml fourth organic solvent for about every 1 ml water.

The aqueous ammonia is preferably added under stirring.

Preferably, an aqueous layer is isolated and then washed with the fourthorganic solvent.

According to a further aspect of the present invention, there isprovided crystalline duloxetine hydrochloride prepared by any of themethods above.

Preferably, the crystalline duloxetine hydrochloride has a purity of atleast 95%, more preferably at least 98%.

Accordingly, the present invention describes a novel crystalline form ofduloxetine hydrochloride and a process to prepare it.

It is anticipated that the crystalline form of duloxetine hydrochloridedisclosed herein will be useful in the treatment of a variety ofdiseases which are prevented, ameliorated or eliminated by theadministration of a serotonin and/or norepinephrine reuptake inhibitor.Examples of such diseases include depression, pain related to diabeticneuropathy and stress urinary incontinence, obesity, alcoholism, loss ofmemory, anxiety and smoking.

According to another aspect of the present invention, there is thereforeprovided a pharmaceutical composition comprising crystalline duloxetinehydrochloride as described herein.

According to a further aspect, there is provided a composition fortreating a disease which is prevented, ameliorated or eliminated by theadministration of a serotonin and/or norepinephrine reuptake inhibitor,the composition comprising crystalline duloxetine hydrochloride asdescribed herein.

Preferably, the disease is selected from depression, pain related todiabetic neuropathy and stress urinary incontinence, obesity,alcoholism, loss of memory, anxiety and smoking.

There is also provided a method of treating a disease which isprevented, ameliorated or eliminated by the administration of aserotonin and/or norepinephrine reuptake inhibitor, the methodcomprising administering to a patient a therapeutically effective amountof crystalline duloxetine hydrochloride as described herein, or of thepharmaceutical composition as described herein.

Preferably, the disease is selected from depression, pain related todiabetic neuropathy and stress urinary incontinence, obesity,alcoholism, loss of memory, anxiety and smoking.

By a therapeutically effective amount, it is meant an amount which iscapable of preventing, ameliorating or eliminating the diseasesmentioned herein.

The crystalline duloxetine hydrochloride can be mixed with a carrier,diluent or excipient therefor, all of which are well known in the art.For example, suitable carriers may include pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols, ointments, soft and hard gelatine capsules, suppositories,sterile injectable solutions and sterile packaged powders.

There are many advantages to providing a crystalline form of duloxetinehydrochloride compared to an amorphous form. A crystalline form of thedrug can be easily purified by crystallisation and recrystallisation.Compared to other methods of purification, it is also cheaper and moreconvenient to perform crystallisation on a large scale. Furthermore, acrystalline form may be more stable than an amorphous form.

BRIEF DESCRIPTION OF THE DRAWINGS

An example of the present invention will now be described in detail withreference the accompanying figures.

FIG. 1 shows the X-ray Diffractometer (XRD) spectrum for the crystallineform of the present invention.

FIG. 2 shows Thermogravimetric Analysis (TGA) and Differential ThermalAnalysis (DTA) thermograms for the crystalline form of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

Duloxetine oxalate salt was initially prepared following the proceduregiven in EP 273658 (corresponding to U.S. Pat. Nos. 5,023,269 and4,956,388, each hereby incorporated by reference). Duloxetine was thenfreed from the oxalic acid and converted directly to its hydrochloridesalt by the introduction of hydrochloride in organic solvent.

The isolated crystalline duloxetine hydrochloride was fullycharacterized by Differential Scanning Calorimetry (DSC), solidcarbon-13 NMR and X-ray powder diffraction.

Crystallization

EXAMPLE 1

Free Duloxetine Preparation

Duloxetine oxalate (38.7 g) was placed into 300 ml of an ethylacetate/water (1:1) mixture. Aqueous ammonium solution was added todissolve the solid completely under stirring. The separated aqueouslayer was washed with ethyl acetate twice. The combined organic solutionwas then washed with saturated brine, and dried with anhydrous sodiumsulphate. The free duloxetine (26 g) was obtained as an oil by removingthe solvents from the filtrate solution.

Crystallization of Duloxetine Hydrochloride:

The free duloxetine (3 g) was first dissolved in dichloromethane (5 ml),then an ethanol solution (2 ml) containing 20% HCl was added at 0° C.with stirring, followed by hexane (40 ml). The crystalline product cameout after the solution was cooled at 0-10° C. for 10 hours. The productwas collected by filtration, washed with hexane and dried (1.8 g, 55%yield, m.p. 148-154° C.). Its purity was 98.4% with an optical purity of99.6%. The DTA result shown m.p. was 160.6° C. The crystalline form,designated as Form III, was thus obtained.

TABLE 1 The XRD spectrum for the crystalline form obtained according toExample 1. 2 theta (degree) I/I₀ D(A) 11.952 64 7.398 13.930 25 6.35114.500 44 6.103 14.759 55 5.997 16.190 35 5.470 17.968 44 4.932 18.62037 4.761 18.820 50 4.711 20.785 52 4.270 21.260 35 4.175 21.438 89 4.14121.760 21 4.081 22.120 71 4.015 22.280 50 3.986 23.080 71 3.850 23.28046 3.817 24.055 100 3.696 26.309 29 3.384 26.940 24 3.306 29.861 292.989

TABLE 2 TGA/DTA parameters Detector DTG-60H Sample Weight 7.428 mgTemperature Rate 10° C. Hold Temperature 300° C. Hold Time 0 min

1. A method for the preparation of crystalline duloxetine hydrochloride,the method comprising: (a) dissolving duloxetine in a first organicsolvent to form a first solution; (b) adding the first solution to asecond organic solvent solution comprising HCl to form a secondsolution; (c) adding the second solution to a third organic solvent toform a third solution; (d) allowing duloxetine hydrochloride tocrystallize out from the solution; and (e) collecting the crystallizedduloxetine hydrochloride, wherein the first organic solvent is a halogensubstituted C₁ to C₆ hydrocarbon.
 2. The method of claim 1, wherein thefirst organic solvent is dichloromethane.
 3. The method of claim 1,wherein the second organic solvent is an alcohol.
 4. The method of claim3, wherein the second organic solvent is ethanol.
 5. The method of claim1, wherein the third organic solvent is a C₁ to C₈ hydrocarbon.
 6. Themethod of claim 5, wherein the third organic solvent is hexane.
 7. Themethod of claim 1, wherein the duloxetine is dissolved in the firstorganic solvent in a ratio of about 5 ml first organic solvent for aboutevery 3 g of duloxetine.
 8. The method of claim 1, wherein the secondorganic solvent comprises about 20% HCl.
 9. The method of claim 1,wherein the first solution is added to the second organic solvent ataround 0° C.
 10. The method of claim 1, wherein the first solution isadded to the second organic solvent with stirring.
 11. The method ofclaim 1, wherein the second solution is added to a volume of the thirdorganic solvent in a ratio of about 40 ml third organic solvent forabout every 3 g of duloxetine used in step (a).
 12. The method of claim1, wherein the duloxetine hydrochloride is allowed to crystallize outfrom the solution during a period of cooling at around 0° C. to around10° C.
 13. The method of claim 1, wherein the duloxetine hydrochlorideis allowed to crystallize out from the solution during a period of about10 hours.
 14. The method of claim 1, wherein the crystallized duloxetinehydrochloride is collected by filtration.
 15. The method of claim 1,wherein the collected crystallized duloxetine hydrochloride is washedand then dried.
 16. The method of claim 15, wherein the collectedcrystallized duloxetine hydrochloride is washed with a C₁ to C₈hydrocarbon.
 17. The method of claim 16, wherein the collectedcrystallized duloxetine hydrochloride is washed with hexane.
 18. Themethod of claim 1, comprising the following additional steps for thepreparation of duloxetine for use in step (a): (i) placing duloxetineoxalate into a solution of a fourth organic solvent and water; (ii)adding aqueous ammonia solution for dissolving the duloxetine oxalate;(iii) isolating a separated organic layer; (iv) washing the organiclayer with saturated brine; (v) drying the organic layer; and (vi)removing the solvents from the organic layer.
 19. The method of claim18, wherein the fourth organic solvent is a C₁ to C₆ ester.
 20. Themethod of claim 19, wherein the fourth organic solvent is ethyl acetate.21. The method of claim 18, wherein duloxetine oxalate is placed into asolution of the fourth organic solvent and water at a ratio of about 300ml fourth organic solvent and water solution for about every 39 g ofduloxetine oxalate.
 22. The method of claim 18, wherein the solution ofa fourth organic solvent and water contains about 1 ml fourth organicsolvent for about every 1ml water.
 23. The method of claim 18, whereinthe aqueous ammonia is added under stirring.
 24. The method of claim 18,wherein an isolated aqueous layer is washed with the fourth organicsolvent.
 25. The method of claim 18, wherein the organic layer is driedwith anhydrous sodium sulphate.